NM_000527.5(LDLR):c.621C>T (p.Gly207=) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Sep 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003945.15

Allele description [Variation Report for NM_000527.5(LDLR):c.621C>T (p.Gly207=)]

NM_000527.5(LDLR):c.621C>T (p.Gly207=)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.621C>T (p.Gly207=)

Other names:

G186G; NP_000518.1:p.Gly207Gly=

HGVS:

NC_000019.10:g.11105527C>T
NG_009060.1:g.21147C>T
NM_000527.5:c.621C>TMANE SELECT
NM_001195798.2:c.621C>T
NM_001195799.2:c.498C>T
NM_001195800.2:c.314-1865C>T
NM_001195803.2:c.314-1038C>T
NP_000518.1:p.Gly207=
NP_000518.1:p.Gly207=
NP_001182727.1:p.Gly207=
NP_001182728.1:p.Gly166=
LRG_274t1:c.621C>T
LRG_274:g.21147C>T
LRG_274p1:p.Gly207=
NC_000019.9:g.11216203C>T
NM_000527.4:c.621C>T
c.621C>T

Protein change:

GLY186GLY

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001228; OMIM: 606945.0066; dbSNP: rs121908044

NCBI 1000 Genomes Browser:

rs121908044

Molecular consequence:

NM_001195800.2:c.314-1865C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1038C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.621C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.621C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.498C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

Recent activity

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palmitoyltransferase ZDHHC6 isoform X2 [Homo sapiens]
palmitoyltransferase ZDHHC6 isoform X2 [Homo sapiens]
gi|1034569276|ref|XP_016872053.1|

Protein
TRAV22 T cell receptor alpha variable 22 [Homo sapiens]
TRAV22 T cell receptor alpha variable 22 [Homo sapiens]
Gene ID:28661

Gene
TRAV26-2 T cell receptor alpha variable 26-2 [Homo sapiens]
TRAV26-2 T cell receptor alpha variable 26-2 [Homo sapiens]
Gene ID:28656

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024110	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2008)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000294826	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000503190	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583711	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000599336	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 18400033
SCV000606170	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000748131	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 18400033
SCV004175481	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848336	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 22, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18400033, 30293936, 28104544, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	9	2	not provided	2601	not provided	clinical testing, literature only
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, research, curation

Citations

PubMed

Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing.

Defesche JC, Schuurman EJ, Klaaijsen LN, Khoo KL, Wiegman A, Stalenhoef AF.

Clin Genet. 2008 Jun;73(6):573-8. doi: 10.1111/j.1399-0004.2008.00999.x. Epub 2008 Apr 8.

PubMed [citation]

PMID:: 18400033

Autosomal dominant hypercholesterolemia in Catalonia: Correspondence between clinical-biochemical and genetic diagnostics in 967 patients studied in a multicenter clinical setting.

Martín-Campos JM, Plana N, Figueras R, Ibarretxe D, Caixàs A, Esteve E, Pérez A, Bueno M, Mauri M, Roig R, Martínez S, Pintó X, Masana L, Julve J, Blanco-Vaca F; Xarxa d’Unitats de Lípids i Arteriosclerosi (XULA)..

J Clin Lipidol. 2018 Nov - Dec;12(6):1452-1462. doi: 10.1016/j.jacl.2018.09.002. Epub 2018 Sep 7.

PubMed [citation]

PMID:: 30293936

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024110.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 35 unrelated Dutch patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in known hypercholesterolemia genes, Defesche et al. (2008) identified a 621C-T transition in exon 4 of the LDLR gene, resulting in a synonymous gly186-to-gly (G186G) change, that introduces a 3-prime splice donor site with a higher 'probability score' than the naturally occurring 3-prime splice site 75 bp downstream. Analysis of cDNA synthesized from total RNA revealed that the aberrant splicing results in a 75-bp in-frame deletion and a stable mRNA, predicted to produce an LDLR protein lacking a 25-amino acid fragment (gly186 to cys210). The variant was found in homozygosity in 2 of the probands, who had LDL cholesterol levels of 14.8 and 10.5 mmol/L, respectively, and who both suffered myocardial infarctions before the age of 20 years. The variant was also identified in 62 first-degree relatives of the index cases.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294826.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503190.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

Description

subject mutated among 2600 FH index cases screened = 5, family member = 1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		5	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583711.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Probable FH

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	2	not provided

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599336.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)
2	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

"Assay Description:Htz patients lymphocytes, RNA assays"

PubMed [ID: 18400033]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606170.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Iberoamerican FH Network, SCV000748131.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

"Assay Description:Htz patients lymphocytes, RNA assays"

PubMed [ID: 18400033]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175481.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848336.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Gly207Gly variant in LDLR has been reported in >30 individuals with familial hypercholesterolemia (FH) and segregated with disease in numerous affected individuals from several families; of note, at least 2 of these individuals were homozygous and displayed features of autosomal recessive FH (Defesche 2008 PMID: 18400033, Durst 2017 PMID: 28104544, Martín-Campos 2018 PMID: 30293936). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 3747) and was absent from large population studies. Computational tools predict a splicing impact and an in vitro analyses supported an alteration of splicing leading to an in-frame deletion of 75 bp (Defesche 2008 PMID: 18400033, Martin-Campos 2018 PMID: 30293936). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PS4, PM2_Supporting, PP1_Strong, PS3_Supporting, PM3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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